U.S. patent number 8,168,632 [Application Number 12/657,924] was granted by the patent office on 2012-05-01 for bicyclic amide derivatives for the treatment of respiratory disorders.
This patent grant is currently assigned to Cortex Pharmaceuticals, Inc.. Invention is credited to Rudolf Mueller, Leslie J. Street.
United States Patent |
8,168,632 |
Mueller , et al. |
May 1, 2012 |
Bicyclic amide derivatives for the treatment of respiratory
disorders
Abstract
This invention relates to compounds, pharmaceutical compositions
and methods for use in the prevention and treatment of disorders of
respiration such as overdose of an alcohol, an opiate, an opioid, a
barbiturate, an anesthetic, or a nerve toxin. In a particular
aspect, the invention relates to bicyclic amide compounds useful
for treatment of such conditions, and methods of using these
compounds for such treatment.
Inventors: |
Mueller; Rudolf (Foothill
Ranch, CA), Street; Leslie J. (Laguna Niguel, CA) |
Assignee: |
Cortex Pharmaceuticals, Inc.
(Irvine, CA)
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Family
ID: |
42312102 |
Appl.
No.: |
12/657,924 |
Filed: |
January 29, 2010 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100173903 A1 |
Jul 8, 2010 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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PCT/US2008/009508 |
Aug 8, 2008 |
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61206642 |
Feb 2, 2009 |
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60964362 |
Aug 10, 2007 |
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Current U.S.
Class: |
514/230.5 |
Current CPC
Class: |
A61P
25/18 (20180101); A61P 25/24 (20180101); A61P
11/00 (20180101); A61P 25/16 (20180101); A61P
11/16 (20180101); A61P 25/00 (20180101); C07D
498/08 (20130101); A61P 25/28 (20180101); A61K
45/06 (20130101); A61K 31/5375 (20130101); A61K
31/5375 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/538 (20060101) |
Field of
Search: |
;514/230.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2012094 |
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Sep 1971 |
|
DE |
|
WO9402475 |
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Feb 1994 |
|
WO |
|
9736907 |
|
Oct 1997 |
|
WO |
|
9835950 |
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Aug 1998 |
|
WO |
|
9921422 |
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May 1999 |
|
WO |
|
9933469 |
|
Jul 1999 |
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WO |
|
WO9942456 |
|
Aug 1999 |
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WO |
|
03099299 |
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Dec 2003 |
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WO |
|
2008025148 |
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Mar 2008 |
|
WO |
|
2008085505 |
|
Jul 2008 |
|
WO |
|
2008085506 |
|
Jul 2008 |
|
WO |
|
2008143963 |
|
Nov 2008 |
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WO |
|
2009023126 |
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Feb 2009 |
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WO |
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2009038752 |
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Mar 2009 |
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WO |
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Other References
Morissette et al. Advanced Drug Delivery Reviews 2004, 56, 275-300.
cited by examiner .
Vippagunta et al., abstract, Vippagunta, Sudha R. "Crystalline
Solids." Advanced Drug Delivery Reviews 48(2001): 3-26. cited by
examiner .
Monaghan et al., in Brain Research 324:160-164 (1984). cited by
other .
Arai and Lynch, Brain Research 598:173-184 (1992). cited by other
.
Granger et al., Synapse 15:326-329 (1993). cited by other .
Staubli et al., PNAS 91:777-781 (1994). cited by other .
Arai et al., Brain Res. 638:343-346 (1994). cited by other .
Staubli et al., PNAS 91:11158-11162 (1994). cited by other .
Shors et al., Neurosci. Let. 186:153-156 (1995). cited by other
.
Larson et al., J. Neurosci. 15:8023-8030 (1995). cited by other
.
Granger et al., Synapse 22:332-337 (1996). cited by other .
Arai et al., JPET 278:627-638 (1996). cited by other .
Lynch et al., Internat. Clin. Psychopharm. 11: 13-19 (1996). cited
by other .
Lynch et al., Exp. Neurology 145:89-92 (1997). cited by other .
Ingvar et al., Exp. Neurology 146:553-559 (1997). cited by other
.
Hampson, et al., J. Neurosci. 18:2748-2763 (1998). cited by other
.
Porrino et al., PLoS Biol 3(9):1639-1652 (2006). cited by other
.
del Cerro and Lynch, Neuroscience 49: 1-6 (1992). cited by other
.
Whitlock et al., Science 313:1093-1097 (2006). cited by other .
Pastalkova, et al., Science 313:1141-1144 (2006). cited by other
.
Rex, et al., J. Neurophysiol. 96:677-685 (2006). cited by other
.
Lauterborn, et al., J. Neurosci. 20:8-21 (2000). cited by other
.
Lauterborn, et al., JPET 307:297-305 (2003). cited by other .
Mackowiak, et al., Neuropharmacology 43:1-10 (2002). cited by other
.
O'Neill, et al., Eur. J. Pharmacol. 486:163-174 (2004). cited by
other .
Kent, et al., Mol. Psychiatry 10:939-943 (2005). cited by other
.
Riikonen, et al., J. Child Neurol. 18:693-697 (2003). cited by
other .
Chang, et al., Neuron 49:341-348 (2006). cited by other .
Ito et al., J. Physiol. 424:533-543 (1990). cited by other .
Staubli et al., Psychobiology 18:377-381 (1990). cited by other
.
Xiao et al., Hippocampus 1:373-380 (1991). cited by other .
Guenzi and Zanetti, J. Chromatogr. 530:397-406 (1990). cited by
other .
Himori, et al., Pharmacology Biochemistry and Behavior 47:219-225
(1994). cited by other .
Pizzi et al., J. Neurochem. 61:683-689 (1993). cited by other .
Nakamura and Shirane, Eur. J. Pharmacol. 380: 81-89 (1999). cited
by other .
Spignoli and Pepeu, Pharmacol. Biochem. Behav. 27:491-495 (1987).
cited by other .
Hall and Von Voigtlander, Neuropharmacology 26:1573-1579(1987).
cited by other .
Kessler et al., Brain Res. 560: 337-341 (1991). cited by other
.
Staubli et al., Hippocampus 2: 49-58 (1992). cited by other .
Sirvio et al., Neuroscience 74: 1025-1035 (1996). cited by other
.
Chapter 7, Neuroscience, edited by Dale Purves, Sinauer Associates,
Inc., Sunderland, MA 1997. cited by other .
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM IV), pp. 317-391. cited by other .
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM IV) Sections 293.81, 293.82, 295.10, 295.20, 295.30,
295.40, 295.60, 295.70, 295.90, 297.1, 297.3, 298.8. cited by other
.
http://www.chemdrug.com/database/10.sub.--3.sub.--gbflimrcjilwki.html.
cited by other .
Gouaux et al.,Structure and function of AMPA receptors. J. Physiol.
2003, 554, 249-253. cited by other .
Gueyrard et al. A new and rapid access to homochiral
2,3-dihydro-oxazolo[2,3-b]quinazolin-5-ones, Tetrahedron:
Assymmetry 2001, 12, 337-340. cited by other .
Murray et al. LY503430, a novel AMPA receptor potentiator with
functional, neuroprotective and neurotrophic effects in rodent
models of Parkinson's disease. J. Pharmacol. Exp. Ther. 2003, 306,
752-762. cited by other .
Russell, Increased AMPA Receptor Function in Slices Containing the
Prefrontal Cortex of Spontaneously Hypertensive Rats. Metabolic
Brain Disease, 2001, 16, 143-149. cited by other .
Pontarelli, New drug that enhances glutamate transmission in brain
being evaluated for fragile X. printed Apr. 10, 2008 from
Http://www.innovations-report.com/html/reports/medicine.sub.--health/repo-
rt-12386.html. cited by other .
Ren. Ampakines alleviate respiratory depression in rats. American
Journal of Respiratory and Critical Care Medicine 2006, 174,
1384-1391. cited by other.
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Primary Examiner: Anderson; Rebecca
Assistant Examiner: Shterengarts; Samantha
Attorney, Agent or Firm: Coleman; Henry D. Sudol; R. Neil
Sapone; William J.
Parent Case Text
RELATED APPLICATIONS
This application claims the benefit of priority of U.S. provisional
application Ser. No. 61/206,642, filed Feb. 2, 2009, entitled
"Bicyclic Amide Derivatives for Enhancing Glutamatergic Synaptic
Responses" and is a continuation-in-part application of
international patent application PCT/US2008/009508 (Published as WO
2009/023126), filed 8Aug. 2008, entitled "Bicyclic Amides for
Enhancing Glutamatergic Synaptic Responses", now U.S. patent
application. Ser. No. 12/733,073, of same title, having a filing
date of Jul. 19, 2010, which claims priority from United States
provisional application US60/964,362 entitled"Bicyclic Amide
Derivatives for Enhancing Glutamatergic Synaptic Responses", filed
Aug. 10, 2007, the entire contents of each of Said applications
being incorporated by reference herein.
Claims
The invention claimed is:
1. A method of treating respiratory depression in a patient in need
thereof, said method comprising administering to said patient an
effective amount of a compound according to formula A: ##STR00012##
wherein: X.dbd.O, or (CH.sub.2).sub.n n=0 or 1, or a
pharmaceutically acceptable salt thereof.
2. The method according to claim 1 wherein said compound is a
structure according to formula B: ##STR00013## or a
pharmaceutically acceptable salt thereof.
3. The method according to claim 1 wherein said compound is a
structure according to formula C: ##STR00014## wherein: X.dbd.O, or
CH.sub.2, or a pharmaceutically acceptable salt thereof.
4. The method according to claim 1 wherein said compound is
2,1,3-benzoxadiazol-5-yl(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methanone,
2,1,3-Benzoxadiazol-5-yl(3-oxa-9-azabicyclo[3.3.1]non-9-yl)methanone
or
2,1,3-Benzoxadiazol-5-yl(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methanone.
5. The method according to claim 1 wherein said compound is
administered in combination with an opiate or opioid analgesic.
6. The method according to claim 1 wherein said compound is
administered in combination with an anesthetic agent.
7. The method according to claim 6 wherein said anesthetic agent is
selected from the group consisting of propofol and
barbiturates.
8. The method according to claim 1 wherein said compound is
administered in combination with an opiate, an opioid analgesic or
an anesthetic agent wherein said anesthetic agent is selected from
the group consisting of propofol and barbiturates.
9. The method according to claim 2 wherein said compound is
administered in combination with an opiate or opioid analgesic.
10. The method according to claim 2 wherein said compound is
administered in combination with an anesthetic agent.
11. The method according to claim 10 wherein said anesthetic agent
is selected from the group consisting of propofol and
barbiturates.
12. The method according to claim 3 wherein said compound is
administered in combination with an opiate or opioid analgesic.
13. The method according to claim 3 wherein said compound is
administered in combination with an anesthetic agent.
14. The method according to claim 13 wherein said anesthetic agent
is selected from the group consisting of propofol and
barbiturates.
15. The method according to claim 4 wherein said compound is
administered in combination with an opiate or opioid analgesic.
16. The method according to claim 4 wherein said compound is
administered in in combination with an anesthetic agent.
17. The method according to claim 16 wherein said anesthetic agent
is selected from the group consisting of propofol and barbiturates.
Description
FIELD OF THE INVENTION
This invention relates to compounds, pharmaceutical compositions
and methods for use in the prevention and treatment of cerebral
insufficiency, including enhancement of receptor functioning in
synapses in brain networks responsible for breathing. Imbalances in
neuronal activities between different brain regions may lead to a
number of disorders, including respiratory depression. In a
particular aspect, the invention relates to compounds useful for
treatment of respiratory depression and methods of using these
compounds for such treatment.
BACKGROUND OF THE INVENTION
The release of glutamate at synapses at many sites in mammalian
forebrain stimulates two classes of postsynaptic ionotropic
glutamate receptors. These classes are usually referred to as AMPA
and N-methyl-D-aspartic acid (NMDA) receptors. AMPA receptors
mediate a voltage independent fast excitatory post-synaptic current
(the fast EPSC), whereas NMDA receptors generate a
voltage-dependent, slow excitatory current. Studies carried out in
slices of hippocampus or cortex, indicate that the AMPA receptor
mediated fast EPSC is generally the dominant component by far at
most glutamatergic synapses, and activation of AMPA receptors is
usually a prerequisite for NMDA receptors activation. AMPA
receptors are expressed throughout the central nervous system.
These receptors are found in high concentrations in the superficial
layers of neocortex, in each of the major synaptic zones of
hippocampus, and in the striatal complex, as reported by Monaghan
et al., in Brain Research 324:160-164 (1984). AMPA receptors are
expressed in brain regions that regulate the inspiratory drive
responsible for control of breathing (Paarmarm et al, Journal of
Neurochemistry, 74: 1335-1345 (2000).
For the reasons set forth above, drugs that modulate and thereby
enhance the functioning of AMPA receptors could have significant
benefits for reversal of respiratory depression induced by
pharmacological agents such as opioids and opiates, or other means.
Drugs that enhance the functioning of the AMPA receptor can
effectively reverse opioid- and barbiturate-induced respiratory
depression without reversing the analgesic response (Ren et al,
American Journal of Respiratory and Critical Care Medicine, 174:
1384-1391 (2006). Therefore these drugs may be useful in preventing
or reversing opioid-induced respiratory depression and for
alleviating other forms of respiratory depression including
sedative use.
Certain substituted [2.1.3] benzoxadiazole compounds have been
found to be significantly more potent in animal models of breathing
disorders than previously disclosed compounds in US 2002/0055508
and US 2002/0099050. This novel class of bicyclic amides (A),
described in greater detail herein, display significant activity
for enhancing AMPA mediated glutamateric synaptic responses.
##STR00001##
SUMMARY OF THE INVENTION
The present invention includes, in one aspect, a compound as shown
by structure A and other structures and described in Section II of
the Detailed Description, which follows. Administration of
compounds of this class has been found to enhance AMPA mediated
glutamatergic synaptic responses in vivo and this assay has proven
useful in assessing the efficacy of compounds in the reversal of
opiod induced respiratory depression. This activity translates into
pharmaceutical compounds and corresponding methods of use,
including treatment methods. Compounds within the present invention
demonstrate improved pharmacokinetic properties compared with
previously described compounds and have good oral
bioavailability.
In another aspect, the invention includes a method for reducing or
inhibiting respiratory depression in a subject having respiratory
depression, comprising administering to the subject an amount of a
compound of the invention, the amount being sufficient to reduce or
inhibit respiratory depression. In one embodiment of the invention,
the subject is a human. In another embodiment, the subject is a
mammal. Also claimed is a method for reducing or inhibiting
respiratory depression comprising administering to the subject an
amount of a compound of the invention in combination with an opioid
analgesic; examples of such opiates include but are not limited to,
alfentanil and fentanyl.
According to the methods, such a subject is treated with an
effective amount of a compound as shown by structure A, and
described in Section II of the Detailed Description, following, in
a pharmaceutically acceptable carrier. These and other objects and
features of the invention will become more fully apparent when the
following detailed description of the invention is read in
conjunction with the accompanying drawings.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
The terms below have the following meanings unless indicated
otherwise. Other terms that are used to describe the present
invention have the same definitions as those terms are generally
used by those skilled in the art.
The term "compound" is used herein to refer to any specific
chemical compound disclosed herein. Within its use in context, the
term generally refers to a single stable compound, but in certain
instances may also refer to stereoisomers and/or optical isomers
(including enantiopure compounds, enantiomerically enriched
compounds and racemic mixtures) of disclosed compounds.
The term "effective amount" refers to the amount of a selected
compound of formula I that is used within the context of its
intended use to effect an intended result, for example, to enhance
glutamatergic synaptic response by increasing AMPA receptor
activity. The precise amount used will vary depending upon the
particular compound selected and its intended use, the age and
weight of the subject, route of administration, and so forth, but
may be easily determined by routine experimentation. In the case of
the treatment of a condition or disease state, an effective amount
is that amount which is used to effectively treat the particular
condition or disease state.
The term "pharmaceutically acceptable carrier" refers to a carrier
or excipient which is not unacceptably toxic to the subject to
which it is administered. Pharmaceutically acceptable excipients
are described at length by E. W. Martin, in "Remington's
Pharmaceutical Sciences."
A "pharmaceutically acceptable salt" of an amine compound, such as
those contemplated in the current invention, is an ammonium salt
having as counter ion an inorganic anion such as chloride, bromide,
iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and the
like, or an organic anion such as acetate, malonate, pyruvate,
propionate, fumarate, cinnamate, tosylate, and the like.
The term "patient" or "subject" is used throughout the
specification to describe an animal, generally a mammalian animal,
including a human, to whom treatment or use with the compounds or
compositions according to the present invention is provided. For
treatment or use with/or of those conditions or disease states
which are specific for a specific animal (especially, for example,
a human subject or patient), the term patient or subject refers to
that particular animal.
The term "brain network" is used to describe different anatomical
regions of the brain that communicate with one another via the
synaptic activity of neuronal cells.
The term "AMPA receptor" refers to an aggregate of proteins found
in some membranes, which allows positive ions to cross the membrane
in response to the binding of glutamate or AMPA
(DL-.alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid),
but not NMDA.
The term "excitatory synapse" is used to describe a cell-cell
junction at which release of a chemical messenger by one cell
causes depolarization of the external membrane of the other cell.
An excitatory synapse describes a postsynaptic neuron which has a
reversal potential that is more positive than the threshold
potential and consequently, in such a synapse, a neurotransmitter
increases the probability that an excitatory post synaptic
potential will result (a neuron will fire producing an action
potential). Reversal potentials and threshold potentials determine
postsynaptic excitation and inhibition. If the reversal potential
for a post synaptic potential ("PSP") is more positive than the
action potential threshold, the effect of a transmitter is
excitatory and produces an excitatory post synaptic potential
("EPSP") and the firing of an action potential by the neuron. If
the reversal potential for a post synaptic potential is more
negative than the action potential threshold, the transmitter is
inhibitory and may generate inhibitory post synaptic potentials
(IPSP), thus reducing the likelihood that a synapse will fire an
action potential. The general rule for postsynaptic action is: if
the reversal potential is more positive than threshold, excitation
results; inhibition occurs if the reversal potential is more
negative than threshold. See, for example, Chapter 7, NEUROSCIENCE,
edited by Dale Purves, Sinauer Associates, Inc., Sunderland, Mass.
1997.
The term "synaptic response" is used to describe biophysical
reactions in one cell as a consequence of the release of chemical
messengers by another cell with which it is in close contact.
The term "impaired" is used to describe a function working at a
level that is less than normal.
Impaired functions can be significantly impacted such that a
function is barely being carried out, is virtually non-existent or
is working in a fashion that is significantly less than normal.
Impaired functions may also be sub-optimal. The impairment of
function will vary in severity from patient to patient and the
condition to be treated.
The term "respiratory depression" as used herein refers to a
variety of conditions characterized by reduced respiratory
frequency and inspiratory drive to cranial and spinal motor
neurons.
Specifically, respiratory depression refers to conditions where the
medullary neural network associated with respiratory rhythm
generating activity does not respond to accumulating levels of
PCO.sub.2 (or decreasing levels of PO.sub.2) in the blood and
subsequently under stimulates motorneurons controlling lung
musculature.
II. Compounds of the Present Invention
The present invention is directed to compounds having the property
of enhancing AMPA receptor function. These include compounds having
the structure A, below:
##STR00002##
wherein:
X.dbd.O, or (CH.sub.2).sub.n
n=0 or 1, or a pharmaceutically acceptable salt, solvate, or
polymorph thereof.
A preferred embodiment includes a compound of formula B, below:
##STR00003## or a pharmaceutically acceptable salt, solvate, or
polymorph thereof.
A further preferred embodiment includes compounds of formula C,
below:
##STR00004##
wherein:
X.dbd.O, or CH.sub.2, or a pharmaceutically acceptable salt,
solvate, or polymorph thereof.
In a further aspect, the present invention provides compounds of
Formula A selected from:
[2,1,3]-benzoxadiazol-5-yl(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methanone,
[2,1,3]-Benzoxadiazol-5-yl(3-oxa-9-azabicyclo[3.3.1]non-9-yl)methanone
and
[2,1,3]-Benzoxadiazol-5-yl(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methanon-
e
III. Synthesis
The synthesis of the compounds of the invention, are preferably
carried out by the following Scheme. Alternative syntheses by
analogy relying on methodology that exists in the art also may be
used. Each compound may be made using the described synthesis by
following the proposed chemistry as presented herein or by making
minor modifications in the synthetic chemistry relying on well
known methods available in the art. The approach to synthesis is
rather facile and may be readily modified within the scope of the
present teachings. Acid chloride 4 is synthesized starting with
4-amino-3-nitrobenzoic acid 1 by firstly oxidizing using bleach to
give intermediate 2 and then reducing with triethyl phosphite
(P(OEt).sub.3) to give benzofurazan carboxylic acid 3. The
carboxylic acid 3 was transformed to the acid chloride 4 by
refluxing with thionyl chloride and a catalytic amount of DMF in
toluene. The carboxylic acid 3 can be transformed into bicyclic
amides A by reaction with the appropriate aminobicycles using
standard coupling conditions like CDI, EDCI, HBTU in a suitable
solvent. Alternatively, acid chloride 4 can be transformed into
bicyclic amides A under standard coupling conditions with bicyclic
amines in the presence of a base for example triethylamine or
aqueous sodium hydroxide, among others in a suitable solvent, for
example dichloromethane.
##STR00005##
IV. Method of Treatment
According to one aspect of the invention, a method is provided for
treating a mammalian subject suffering from deficiencies in the
number or strength of excitatory synapses or in the number of AMPA
receptors.
The invention provides a method for reducing or inhibiting
respiratory depression in a subject having such a condition,
comprising administering to the subject an amount of a compound of
the invention, the amount being sufficient to reduce or inhibit
respiratory depression. In a further aspect of the invention, a
method is provided for reducing or inhibiting respiratory
depression comprising administering to the subject an amount of a
compound of the invention in combination with an opiate; examples
of such opiates include but are not limited to, alfentanil and
fentanyl.
In the present invention, the method of treatment comprises
administering to the subject in need of treatment, in a
pharmaceutically acceptable carrier, an effective amount of a
compound having the Formula A below:
##STR00006##
wherein:
X.dbd.O, or (CH.sub.2).sub.n
n=0 or 1, or a pharmaceutically acceptable salt, solvate, or
polymorph thereof.
V. Biological Activity
Enhancement of AMPA Receptor Function In Vivo.
Synaptic responses mediated by AMPA receptors are increased
according to the method of the invention, using the compounds
described herein.
The electrophysiological effects of the invention compounds were
tested in vivo in anesthetized animals according to the following
procedures. Animals are maintained under anesthesia by
phenobarbital administered using a Hamilton syringe pump.
Stimulating and recording electrodes are inserted into the
perforant path and dentate gyrus of the hippocampus, respectively.
Once electrodes are implanted, a stable baseline of evoked
responses are elicited using single monophasic pulses (100 .mu.s
pulse duration) delivered at 3/min to the stimulating electrode.
Field EPSPs are monitored until a stable baseline is achieved
(about 20-30 min), after which a solution of test compound is
injected intraperitoneally and evoked field potentials are
recorded. Evoked potentials were recorded for approximately 2 h
following drug administration or until the amplitude of the field
EPSP returns to baseline. In the latter instance, it is common that
an iv administration is also carried out with an appropriate dose
of the same test compound. Invention compounds were assayed in the
in vivo electrophysiology assay described above and data for
representative test compounds is shown in the Table.
TABLE-US-00001 TABLE Compound Example Number .sup.1In vivo
Electrophysiology 1 17% 2 16% 3 15% .sup.1% increase in the
amplitude of the field EPSP in the dentate gyrus of rat @ 10 mpk
i.p. NT = Not tested
VI. Administration, Dosages, and Formulation
Generally, dosages and routes of administration of the compound
will be determined according to the size and condition of the
subject, according to standard pharmaceutical practices. Dose
levels employed can vary widely, and can readily be determined by
those of skill in the art. Typically, amounts in the milligram up
to gram quantities are employed. The composition may be
administered to a subject by various routes, e.g. orally,
transdermally, perineurally or parenterally, that is, by
intravenous, subcutaneous, intraperitoneal, or intramuscular
injection, among others, including buccal, rectal and transdermal
administration. Subjects contemplated for treatment according to
the method of the invention include humans, companion animals,
laboratory animals, and the like.
Formulations containing the compounds according to the present
invention may take the form of solid, semi-solid, lyophilized
powder, or liquid dosage forms, such as, for example, tablets,
capsules, powders, sustained-release formulations, solutions,
suspensions, emulsions, suppositories, creams, ointments, lotions,
aerosols, patches or the like, preferably in unit dosage forms
suitable for simple administration of precise dosages.
Pharmaceutical compositions according to the present invention
comprise an effective amount of one or more compounds according to
the present invention and typically include a conventional
pharmaceutical carrier or excipient and may additionally include
other medicinal agents, carriers, adjuvants, additives and the
like. Preferably, the composition will be about 0.5 to 75% by
weight or more of a compound or compounds of the invention, with
the remainder consisting essentially of suitable pharmaceutical
excipients. For oral administration, such excipients include
pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate, sodium saccharine, talcum, cellulose, glucose, gelatin,
sucrose, magnesium carbonate, and the like. If desired, the
composition may also contain minor amounts of non-toxic auxiliary
substances such as wetting agents, emulsifying agents, or
buffers.
Liquid compositions can be prepared by dissolving or dispersing the
compounds (about 0.5% to about 20% by weight or more), and optional
pharmaceutical adjuvants, in a carrier, such as, for example,
beta-hydroxypropylcyclodextrin, aqueous saline, aqueous dextrose,
glycerol, or ethanol, to form a solution or suspension. For use in
oral liquid preparation, the composition may be prepared as a
solution, suspension, emulsion, or syrup, being supplied either in
liquid form or a dried form suitable for hydration in water or
normal saline.
When the composition is employed in the form of solid preparations
for oral administration, the preparations may be tablets, granules,
powders, capsules or the like. In a tablet formulation, the
composition is typically formulated with additives, e.g. an
excipient such as a saccharide or cellulose preparation, a binder
such as starch paste or methyl cellulose, a filler, a
disintegrator, and other additives typically used in the
manufacture of medical preparations.
An injectable composition for parenteral administration will
typically contain the compound in a suitable i.v. solution, such as
sterile physiological salt solution. The composition may also be
formulated as a suspension in a lipid or phospholipid, in a
liposomal suspension, or in an aqueous emulsion.
Methods for preparing such dosage forms are known or will be
apparent to those skilled in the art; for example, see Remington's
Pharmaceutical Sciences (17th Ed., Mack Pub. Co., 1985). The
composition to be administered will contain a quantity of the
selected compound in a pharmaceutically effective amount for
effecting increased AMPA receptor currents in a subject.
The following examples illustrate but are not intended in any way
to limit the invention. Unless otherwise stated, all temperatures
are given in degrees Celsius. Unless otherwise stated, all NMR
spectra are .sup.1H NMR spectra and were obtained in
deuterochloroform or deuterated DMSO as solvent using
tetramethylsilane as an internal standard. All names of Example
compounds conform to IUPAC nomenclature as provided by the computer
software ChemSketch by ACD Labs.
I. Chemical Methods
INTERMEDIATE 1
[2,1,3]-Benzoxadiazole-5-carboxylic acid
##STR00007##
In a 3 L reactor fitted with mechanical stirring, reflux condenser,
thermometer and nitrogen inlet, KOH (72.46 g) was dissolved in
ethanol (250 ml) and water (250 ml). 4-Amino-3-nitrobenzoic acid
(100 g) was added and the orange suspension was heated to
65-70.degree. C. within 30 minutes. The resulting suspension was
stirred at the same temperature for 45 minutes and cooled to
0.degree. C..+-.5.degree. C. within 30 minutes. A commercially
available (13% w/w) solution of sodium hypochlorite (448.93 g) was
added drop wise within 1.5 hours at 0.degree. C..+-.5.degree. C.
The reaction mixture was stirred at the same temperature for 2
hours and controlled by TLC (CHCl.sub.3 100/acetone 2/ acetic acid
1). Water (350 ml) was added within 15 minutes at 0.degree.
C..+-.5.degree. C. to give a fine yellow suspension. The reaction
mixture was then acidified with a 6N HCl solution (239 ml) until
0.5<pH<1 was reached. NaCl (58.44 g) was added and the
resulting suspension was stirred at 0.degree. C..+-.5.degree. C.
for 1.5 hours under nitrogen. The solid was collected by
filtration, washed with 3.times.400 ml water and dried (40.degree.
C., 30 mbars, 12 hours) to yield 83.6 g (88.8% yield) of
[2,1,3]-benzoxadiazole-5-carboxylic acid N-oxide.
In a 2 L reactor fitted with mechanical stirring, thermometer,
addition funnel, reflux condenser and nitrogen inlet,
[2,1,3]-benzoxadiazole-5-carboxylic acid N-oxide (80 g) was
dissolved in absolute ethanol (800 ml). To this solution triethyl
phosphite (114.05 g) was added within 10 minutes at 70.degree.
C..+-.2.degree. C. The resulting mixture was heated to reflux
(76-78.degree. C.) and maintained for 2 hours. TLC monitoring
(CHCl.sub.3 100/acetone 2/acetic acid 1) showed complete reaction.
The solvent was removed under vacuum (30 mbars, 40.degree. C.)
which yielded a black oil (180 g). Water (400 ml) was added and the
mixture was extracted with ethyl acetate (400 and 160 ml). The
organic phase was extracted with 850 ml water containing NaOH
(9.5<pH<10). The aqueous phase was separated and extracted
with ethyl acetate (3.times.240 ml). The aqueous phase was
acidified (78 ml 6 N HCl) to 1<pH<2 at 5.degree.
C..+-.2.degree. C. which re the crystallization of the yellow
product, which was filtered off and dried (40.degree. C., 30 mbars,
12 hours) to yield 65.56 g (90% yield)
[2,1,3]-benzoxadiazole-5-carboxylic acid: mp=160-161.degree. C.,
.sup.1H NMR (300 MHz, DMSO) .delta. 13.8 (s, 1H); 8.57 (s, 1H);
8.56 (d, 1H, J=0.6 Hz); 7.87 ppm (d, 1H, J=0.6 Hz).
INTERMEDIATE 2
[2,1,3]-Benzoxadiazole-5-carbonylchloride
##STR00008##
In a 500 ml reactor fitted with mechanical stirring, thermometer,
addition funnel, reflux condenser and nitrogen inlet,
[2,1,3]-benzoxadiazole-5-carboxylic acid (28 g) was suspended in
toluene (245 ml). To this suspension was added thionyl chloride
(39.4 g) and DMF (0.35 ml). The resulting mixture was heated to
reflux and maintained for 3 hours. A short pass column was
installed and toluene was distilled (atmospheric pressure, 124 ml)
off to remove excess reagent. After cooling the remaining toluene
was distilled off, which resulted in a thick oil. This oil was
distilled (90.degree. C., 2 mm Hg) to remove impurities and the
product crystallized on standing (79.8% yield), mp: 55-58.degree.
C.
EXAMPLE 1
[2,1,3]-Benzoxadiazol-5-yl(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methanone
##STR00009##
Cis-1-Benzyl-2,5-(dihydroxymethyl)pyrrolidine hydrochloride (3.0 g,
13.5 mmol, see: U.S. Pat. No. 7,012,074) was dissolved in
concentrated H.sub.2SO.sub.4 (10 ml) and heated to 120.degree. C.
for 9 hours. The cooled solution was basified with 10N NaOH (to pH
10) and extracted with ethyl acetate (2.times.100 ml). The organic
phase was dried over sodium sulfate, and concentrated under vacuum
to yield 1.5 g of a colorless oil. The preceding product was
dissolved in dichloromethane (50 ml) and methanol (50 ml), and 10%
Pd/C (0.5 g) was added. The mixture was hydrogenated at 60 psi over
night. The solids were filtered off, a solution of HCl in dioxane
(2 ml, 4N) was added and the solvent evaporated. The residue was
dissolved in dichloromethane (100 ml) and triethylamine (3 ml) and
a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (1.27 g, 7
mmol) in dichloromethane (10 ml) was added. After stirring the
mixture for 0.3 h, water (100 ml) and HCl (.fwdarw.pH2) were added
and the organic phase washed with sodium bicarbonate solution (100
ml), dried over magnesium sulfate, and concentrated under vacuum.
The material was purified by silica gel chromatography eluting with
hexane/THF (60/40), to give after crystallization from
dichloromethane/MTBE 847 mg of the title compound as a white solid:
mp=139-140.degree. C., LC-MS, MH.sup.+=260.2; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.96-7.92 (m, 2H); 7.56-7.52 (m, 1H); 4.82-4.69
(s, 1H); 4.06-3.60 (m, 5H); 2.18-1.95 ppm (m, 4H).
EXAMPLE 2
[2,1,3]-Benzoxadiazol-5-yl(3-oxa-9-azabicyclo[3.3.1]non-9-yl)methanone
##STR00010##
9-Benzyl-3-oxa-9-azabicyclo-(3.3.1)nonane (3.0 g, 13.8 mmol, see:
WO 03004503) was dissolved in ethanol (100 ml), and 10% Pd/C (0.56
g) was added. The mixture was hydrogenated at 100 psi over night.
The solids were filtered off, a solution of HCl in dioxane (4 ml,
4N) was added and the solvent evaporated. The residue was dissolved
in dichloromethane (100 ml) and triethylamine (8 ml) and a solution
of [2,1,3]-benzoxadiazole-5-carbonylchloride (3.5 g, 19.2 mmol) in
dichloromethane (10 ml) was added. After stirring the mixture for
20 minutes, water (100 ml) and H.sub.2SO.sub.4 (.fwdarw.pH2) were
added and the organic phase washed with sodium bicarbonate solution
(100 ml), the aqueous was re-extracted with dichloromethane (100
ml) and the combined organic phase was dried over magnesium
sulfate, and concentrated under vacuum. The crude material was
purified by silica gel chromatography eluting with hexane/THF
(70/30). The product crystallized, when the solvent was evaporated
slowly, which yielded the title compound as a white solid (3.13 g):
mp=128-130.degree. C., LC-MS, MH.sup.+=274.2; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.94 (dd, 2H, J=9.0 and 1.2 Hz); 7.89 (t, 1H,
J=1.2 Hz); 7.47 (dd, 1H, J=9.0 and 1.2 Hz); 4.62 (s, 1H); 4.05 (d,
1H, J=11.7 Hz); 3.95-3.89 (m, 2H); 3.79 (d, 1H, J=11.7 Hz); 3.66
(s, 1H); 2.71-2.54 (m, 1H); 2.14-1.69 ppm (m, 5H).
EXAMPLE 3
[2,1,3]-Benzoxadiazol-5-yl(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)methanone
##STR00011##
9-Benzyl-3,7-dioxa-9-azabicyclo-(3.3.1)nonane (650 mg, 2.96 mmol,
see: JOC, Vol. 71, No. 1, 2006, 413-415) was dissolved in methanol
(20 ml) and formic acid (4 ml). 10% Pd/C (0.3 g) was added and the
mixture was hydrogenated over night. The solids were filtered off,
and the solvent evaporated. The residue was dissolved in methanol
(20 ml) and a solution of HCl in dioxane (2 ml, 4N) was added and
the solvent evaporated. The residue was dissolved in
dichloromethane (80 ml), THF (20 ml) and triethylamine (3 ml) and a
solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (1.0 g, 5.5
mmol) in dichloromethane (10 ml) was added. After stirring the
mixture for 0.5 h, water (100 ml) and H.sub.2SO.sub.4 (.fwdarw.pH2)
were added and the organic phase extracted with sodium bicarbonate
solution (100 ml), the aqueous was re-extracted with
dichloromethane (50 ml) and the combined organics were dried over
magnesium sulfate, and concentrated under vacuum. The crude product
was purified by silica gel chromatography eluting with hexane/THF
(50/50). The product was crystallized from dichloromethane/ethanol,
which gave the title compound as an off white solid (590 mg):
mp=197-199.degree. C., LC-MS, MH.sup.+=276.2; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.98 (dd, 2H, J=9.0 and 1.2 Hz); 7.94 (t, 1H,
J=1.2 Hz); 7.50 (dd, 1H, J=9.0 and 1.2 Hz); 4.52 (s, 2H); 4.21 (d,
2H, J=11.4 Hz); 4.09-4.02 (m, 4H); 3.90 (dd, 2H, J=10.8 and 2.4
Hz); 3.61 ppm (s, 2H).
II. Biological Methods
In Vivo Electrophysiology
The electrophysiological effects of invention compounds were tested
in vivo in anesthetized animals according to the following
procedures.
Animals are maintained under anesthesia by phenobarbital
administered using a Hamilton syringe pump. Stimulating and
recording electrodes are inserted into the perforant path and
dentate gyrus of the hippocampus, respectively. Once electrodes are
implanted, a stable baseline of evoked responses are elicited using
single monophasic pulses (100 .mu.s pulse duration) delivered at
3/min to the stimulating electrode. Field EPSPs are monitored until
a stable baseline is achieved (about 20-30 min), after which a
solution of test compound is injected intraperitoneally and evoked
field potentials are recorded. Evoked potentials are recorded for
approximately 2 h following drug administration or until the
amplitude of the field EPSP returns to baseline. In the latter
instance, it is common that an iv administration is also carried
out with an appropriate dose of the same test compound.
While the invention has been described with reference to specific
methods and embodiments, it will be appreciated that various
modifications may be made without departing from the invention.
* * * * *
References